Fri Sep 23 2022

86 articles - From Friday Sep 16 2022 to Friday Sep 23 2022

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Guidelines

Guidelines, position statements, white papers, technical reviews, consensus statements, etc…


Meta-analysis

meta-analyses and systematic reviews


Original articles

RCT, clinical trials, retrospective studies, etc…

Am J Hematol

Effect of Mutation Allele Frequency on the Risk Stratification of Myelodysplastic Syndrome Patients.

Furthermore, patients harboring U2AF1 mutation might benefit from hypomethylating agents. This study demonstrated the critical role of VAF of mutations for risk stratification in MDS patients and may be incorporated in novel scoring systems.

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Implications of RAS Mutational Status in Subsets of Patients with Newly Diagnosed Acute Myeloid Leukemia Across Therapy Subtypes.

Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = 0.001) and HR 1.7 (95% CI: 0.9-3.1; p = 0.06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS.

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Ann Oncol

Analysis of rare disruptive germline mutations in 2,135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

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Blood

A MIR17HG-derived Long Noncoding RNA Provides an Essential Chromatin Scaffold for Protein Interaction and Myeloma Growth.

Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent anti-tumor effects both in vitro and in vivo in three pre-clinical animal models, including a clinically relevant PDX-NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.

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Breakthrough COVID-19 in vaccinated patients with hematologic malignancies: results from EPICOVIDEHA survey.

Death rate was lower in patients who received monoclonal antibodies, alone or in combination with antivirals. EPICOVIDEHA ( National Clinical Trials identifier NCT04733729) is an international open web-based registry for patients with HMs infected with SARS-CoV-2.

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Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia.

Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at as #NCT02034110.

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Efficacy of JAK 1/2 inhibition in murine immune bone marrow failure.

RUX only modestly suppressed lymphoid and erythroid hematopoiesis in normal and irradiated CByB6F1 mice. Our data supports clinical trials of JAK/STAT inhibitors in human AA and other immune bone marrow failure syndromes.

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Genomic Profiling for Clinical Decision Making in Myeloid Neoplasms and Acute Leukemia.

The 2022 International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias makes extensive use of genomic data. This report aims to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with these hematologic neoplasms.

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Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signalling in cutaneous T-cell lymphoma.

Taken together, these findings indicate that malignant T cells secrete cytokines, which induce skin barrier defects through a JAK1/STAT3 dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for CTCL patients with advanced disease and a compromised skin barrier.

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Missense mutations in PIEZO1, encoding the Piezo1 mechanosensor protein, define the Er red blood cell antigens.

Anti-Er4 and anti-Er5 are implicated in severe hemolytic disease of the fetus and newborn (HDFN). Demonstration of Piezo1, present at just a few hundred copies on the surface of the red blood cell, as the site of a new blood group system highlights the potential antigenicity of even low abundance membrane proteins and contributes to our understanding of the in vivo characteristics of this important and widely studied protein in transfusion biology and beyond.

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MRD dynamics during maintenance for improved prognostication of 1280 myeloma patients in TOURMALINE-MM3 and -MM4 trials.

We demonstrate the limited prognostic value of a single timepoint MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD- status as a relevant endpoint during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD- status.

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Outcomes of patients with aggressive B-Cell lymphoma after failure of anti-CD19 CAR T-Cell Therapy: A DESCAR-T analysis.

In multivariate analysis, predictors of OS were high LDH at infusion, time to CAR-T failure

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Recombinant Erwinia Asparaginase (JZP458) in Acute Lymphoblastic Leukemia: Results from the Phase 2/3 AALL1931 Study.

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 86/167 (51%) patients; TRAEs leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Study results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with those of other asparaginases.

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Tracing the evolutionary history of blood cells to the unicellular ancestor of animals.

We finally showed that, in murine hematopoiesis, repression of CEBPa to maintain non-phagocytic lineages is commonly achieved by polycomb complex. These findings indicate that the initial blood cells emerged inheriting a unicellular organism program driven by CEBPa and that the program has been also seamlessly inherited in phagocytes of various animal species throughout evolution.

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von Willebrand Factor-binding aptamer rondoraptivon pegol as treatment for severe and non-severe hemophilia A.

Rondoraptivon pegol is a first-in-class pro-hemostatic molecule that extended ~3-fold the half-life of substituted FVIII and increased ~2-fold endogenous FVIII levels in hemophilia patients. (NCT04677803).

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Blood Adv

A transcriptome analysis of basal and stimulated VWF release from endothelial cells derived from type 1 VWD patients.

We have shown for the first time that transcriptome-wide differences exist between Type 1 VWD and control ECFCs. These differences may contribute to bleeding in Type 1 VWD, and further investigation may reveal novel biomarkers and therapeutic targets.

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Genome-wide CRISPR/Cas9 Screen Identifies Etoposide Response Modulators Associated with Outcomes in Pediatric AML.

Our results confirmed the involvement of well-characterized genes, including TOP2A and ABCC1, as well as identified novel genes such as RAD54L2, PRKDC, and ZNF451 that have potential to be novel drug targets. This study demonstrates the ability for leveraging CRISPR/cas9 screening in conjunction with clinically relevant endpoints to make meaningful discoveries for the identification of prognostic biomarkers and novel therapeutic targets to overcome treatment resistance.

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Haplotype sequence collection of ABO blood group alleles by long-read sequencing reveals putative A1-diagnostic variants.

Overall, our sequencing strategy proved powerful for producing high-quality ABO haplotypes and holds promise for generating similar collections for other blood groups. The publicly available collection of 154 haplotypes will serve as a valuable resource for molecular analyses of ABO, as well as studies about function and evolutionary history of ABO.

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Hodgkin lymphoma and female fertility: a multicenter study in women treated with ABVD.

The number of pregnancies, births and the time to start a pregnancy in young women treated with ABVD for HL is not different to that of controls. Therefore, female with HL and treated by ABVD should be reassured in regards to fertility.

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Lineage-switching of the cellular distribution of BRAFV600E in multisystem Langerhans cell histiocytosis.

The highest level of mutation occurred in naïve CD4+ T cells (median 51.2%; range 3.8-93.5%). This study reveals an unexpected lineage-switch of BRAFV600E mutation in high risk LCH, which may influence monitoring strategies for the potential withdrawal of inhibitor treatment and has new implications for the pathogenesis of neurodegeneration, which occurred in 4 patients.

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Novel antimyeloma therapeutic option with inhibition of the HDAC1-IRF4 axis and PIM kinase.

Class I HDAC and PIM kinase inhibitors cooperatively suppressed MM cell growth in the presence of IL-6 and in vivo. Therefore, the present results demonstrate the potential of the simultaneous targeting of the intrinsic HDAC1-IRF4 axis plus externally activated PIM2 as an efficient therapeutic option for MM fostered in bone marrow.

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Patient perspectives on testing for clonal hematopoiesis of indeterminate potential.

Our findings highlight the importance of effective risk communication and adequate psychosocial support when considering biomarkers of future risks in cancer survivors. This trial is registered at as NCT01468246.

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Thromboembolic events, bleeding, and mortality in patients with cerebral venous thrombosis: a nationwide cohort study.

Risks were not elevated for myocardial infarction. Clinicians should be aware of the importance of age and sex heterogeneity in the prognosis of CVT.

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Tracking the Progeny of Virus-specific T-cell Products in Patients Post-Transplant using TCR-Sequencing.

Additionally, we demonstrated persistence of virus-specific T cells derived from the T-cell products in most patients who did not show viral reactivations. This study demonstrates that virus-specific T cells from prophylactically infused multi-antigen-specific T-cell products can expand in response to antigen encounter in vivo and even persist in the absence of early viral reactivations.

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U2AF1 and EZH2 mutations are associated with nonimmune hemolytic anemia in myelodysplastic syndromes.

Somatic mutations encoding splicing factors may affect erythrocyte membrane components, biochemical properties, and RBC metabolic function, which underpin the development of atypical clones from erythroid precursors in MDS presenting with hemolysis. Future studies will explore the contribution of altered splicing to the development of acquired hemoglobinopathies.

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Blood Cancer J

Paraskeletal and extramedullary plasmacytomas in multiple myeloma at diagnosis and at first relapse: 50-years of experience from an academic institution.

In the relapsed setting, a significant survival benefit was observed beyond the year 2000, but still with significant differences among patients without Ps, PPs and EMPs (37 vs 22 vs 16months, p=0.003). Importantly, rescue therapy with combinations of proteasome-inhibitors plus immunomodulatory drugs was associated with prolonged OS from first relapse (over 6years), even in patients with EMPs.

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Haematologica

Clinical impact of clonal hematopoiesis on severe COVID-19 patients without canonical risk factors.

Not available.

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Contribution of measurable residual disease status to prediction accuracy of relapse and survival in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation.

Not available.

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Donor cell-derived myelofibrosis relapse after allogeneic stem cell transplantation.

Not available.

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Genome-wide CRISPR screens identify ferroptosis as a novel therapeutic vulnerability in acute lymphoblastic leukemia.

Detailed molecular analysis of B-ALL cells suggest that they are primed to undergo ferroptosis as they exhibit high steady-state oxidative stress potential, a low buffering capacity, and a disabled GPX4-independent secondary lipid peroxidation detoxification pathway. Finally, we validated the sensitivity of B-ALL to ferroptosis induction using patient-derived B-ALL samples.

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Mitigation of gastrointestinal graft versus host disease with tocilizumab prophylaxis is accompanied by preservation of microbial diversity and attenuation of enterococcal domination.

Not available.

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Rituximab therapy after pediatric hematopoietic stem cell transplantation can cause prolonged B cell impairment and increases the risk for infections - a retrospective matched cohort study.

Not available.

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Small molecule SUMO inhibition for biomarker-informed B-cell lymphoma therapy.

Specifically, SUMOi increased the number of memory B-cells as well as cytotoxic and memory T-cells, subsets that are attributed a key role within a coordinated antitumor immune response. In summary, our data constitute pharmacologic SUMOi as a powerful therapy in a subset of B-cell lymphomas causing massive remodeling of the normal B-cell and T-cell compartment.

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Von Willebrand factor in the plasma and in the tumor tissue predicts cancerassociated thrombosis and mortality.

Not available.

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J Hematol Oncol

Elraglusib (9-ING-41), a selective small-molecule inhibitor of glycogen synthase kinase-3 beta, reduces expression of immune checkpoint molecules PD-1, TIGIT and LAG-3 and enhances CD8+ T cell cytolytic killing of melanoma cells.

These data highlight the potential of elraglusib as an immune-modulatory agent and demonstrate the benefit of a sequential approach with immune checkpoint inhibition followed by GSK-3ß inhibition in melanoma and provide a rationale for clinical investigation of elraglusib combined with immune checkpoint inhibitory molecules, including those targeting PD-1, TIGIT and LAG-3. This has several potential implications for current immunotherapy regimes, including possibly reducing the intensity of anti-PD-1 mAb treatment needed for response in patients receiving elraglusib, especially given the benign adverse event profile of elraglusib observed to date. Based on these data, a clinical study of elraglusib, an anti-PD-1 mAb and chemotherapy is ongoing (NCT NCT05239182).

Pubmed   Journal   ReadQx   PMC

Lancet Haematol

Postnatal treatment for children with fetal and neonatal alloimmune thrombocytopenia: a multicentre, retrospective, cohort study.

Our data suggest that HPA-matched transfusions lead to a larger median platelet count increment than HPA-unmatched transfusions, but whether HPA matching is also associated with a reduced risk of bleeding remains unknown. Funding Sanquin.

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Leukemia

A primary hierarchically organized patient-derived model enables in depth interrogation of stemness driven by the coding and non-coding genome.

A novel non-coding regulatory element was identified with a new computational approach using functionally validated primary AML LSC fractions and its role in LSC stemness validated through efficient CRISPR editing using methods optimized for OCI-AML22 LSC. Collectively, OCI-AML22 constitutes a valuable resource to uncover mechanisms governing CSC driven malignancies.

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Compartment-specific mutational landscape of clonal hematopoiesis.

Patients with overt myeloid malignancies showed higher mutation numbers and allele frequencies and a shifting mutation landscape, notably characterized by increasing prevalence of DNMT3A codon R882 variants. Collectively, our data provide novel insights into the genetics, evolution, and spatial and lineage-specific BM involvement of CH.

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Impact of conditioning chemotherapy on lymphocyte kinetics and outcomes in LBCL patients treated with CAR T-cell therapy.

The impact of CCT on lymphocyte count is affected by use of bridging therapy but change in lymphocyte count is independently associated with efficacy. Studies aimed at investigating macrophage biology in this setting may suggest strategies to increase the efficacy of CCT and improve outcomes.

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Thromb Haemost

Dual specificity tyrosine phosphorylation regulated kinase 1B inhibition promotes megakaryocyte polyploidization and platelet production.

In summary, DYRK1B plays an important role in megakaryocyte maturation and platelet production by interacting with cyclin D1 and P27. DYRK1B inhibition has potential therapeutic value in transient thrombocytopenia treatment.

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Uric Acid induces a pro-atherothrombotic phenotype in human endothelial cells by imbalancing TF/TFPI pathway.

The present in vitro study, shows that one of the mechanisms by which high levels of UA contributes to ED might be the imbalance between TF/TFPI levels in endothelial cells, shifting them to a non-physiological, pro-thrombotic phenotype. These UA effects might hypothetically explain, at least in part, the relationship observed between elevated plasma levels of UA and cardiovascular events.

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Reviews&Editorials

Plenty of the editorials are available as full text through the publisher website using the provided link

Am J Hematol

Approach to a patient with "double refractory" chronic lymphocytic leukemia: "Double, double toil and trouble" (Shakespeare).

We further examine the mechanism of resistance to these targeted agents and discuss the current landscape for managing this patient population. Finally, we explore data supporting promising new agents, including non-covalent BTKi, chimeric antigen receptor T cells, and additional classes of agents currently in development.

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Management of front line chronic lymphocytic leukemia.

Although these agents have usually manageable side effects, toxicities might limit choices for the individual patient. We here discuss latest trial data and propose a treatment algorithm for frontline treatment of CLL according to fitness and relevant genetic risk factors like IGHV mutational status and TP53 aberrations.

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Management of relapsed/refractory Chronic Lymphocytic Leukemia.

We will also discuss important considerations when sequencing these available treatments. The recent advances in this disease are significant steps forward, and raise new questions of how these available drugs should be given as well as how we can continue to improve the treatment of CLL.

Pubmed   Journal   ReadQx 

Ann Oncol

The prognostic value of TILs in stage III colon cancer must consider sidedness.

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Blood

AML relapse after a TIGIT race.

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Diffuse myocardial fibrosis as an SCD biomarker.

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GVHD: pDCs providing VIP protection.

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How thinly can one slice the AML diagnostic pie?

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iTPP: nature vs nurture?

Pubmed   Journal   ReadQx 

Mutant CALR's "sweet tooth".

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Predicting the future in MCL with MRD.

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Tet2 helps blood cells balance in air.

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Tranexamic acid as a stopgap for low platelets?

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J Hematol Oncol

Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets.

g., 3,10-dibromofascaplysin combined with olaparib) to exhibit therapeutic potential against various cancers by regulating RCD subroutines. In short, the information provided in this review on the regulation of cell death by indole alkaloids against different targets is expected to be beneficial for the design of novel molecules with greater targeting and biological properties, thereby facilitating the development of new strategies for cancer therapy.

Pubmed   Journal   ReadQx   PMC

TGF-ß signaling in the tumor metabolic microenvironment and targeted therapies.

Then, we review the metabolic reprogramming in the TMME and elaborate on the contribution of TGF-ß to metabolic rewiring at the cellular (intracellular), tissular (intercellular), and organismal (cancer-host) levels. Furthermore, we propose three potential applications of targeting TGF-ß-dependent mechanism reprogramming, paving the way for TGF-ß-related antitumor therapy from the perspective of metabolism.

Pubmed   Journal   ReadQx   PMC

Leukemia

All that glitters is not LGL Leukemia.

However, from a clinical perspective, the relationships between T-LGLL and other borderline and overlapping conditions, including reactive cell expansions, clonal hematopoiesis of indeterminate potential (CHIP) and unrelated clonopathies are not fully established, sometimes making the diagnosis of T cell malignancy challenging. In this review specifically focused on the topic of clonality of T-LGL disorders we will discuss the rationale of the appropriate steps to aid in distinguishing LGLL from its mimics, also attempting to provide new clues to stimulate further investigations designed to move this field forward.

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Miscellaneous

misc publications eg case reports, tools of the trade, images of the month, etc…

Am J Hematol

Neutrophilic Eccrine Hidradenitis in a pediatric patient with Acute Myeloid Leukemia.

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Blood

Berzuini A, Bianco C, Paccapelo C, et al. Red cell-bound antibodies and transfusion requirements in hospitalized patients with COVID-19. Blood. 2020;136(6):766-768.

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Cannabidiol attenuates hyperalgesia in a mouse model of sickle cell disease.

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Caulier A, Sankaran VG. Molecular and cellular mechanisms that regulate human erythropoiesis. Blood. 2022;139(16):2450-2459.

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Duault C, Kumar A, Taghi Khani A, et al. Activated natural killer cells predict poor clinical prognosis in high-risk B- and T-cell acute lymphoblastic leukemia. Blood. 2021;138(16):1465-1480.

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Elsaid R, Meunier S, Burlen-Defranoux O, et al. A wave of bipotent T/ILC-restricted progenitors shapes the embryonic thymus microenvironment in a time-dependent manner. Blood. 2021;137(8):1024-1036.

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Funk CR, Wang S, Chen KZ, et al. PI3Kd/ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity. Blood. 2022;139(4):523-537.

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Gelatinous transformation of bone marrow and concomitant fungal infection in a patient with HIV.

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Introduction to the How I Treat Series on "How I Manage High-Risk Patients Following Allogeneic Transplant".

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iPLAT1: The first-in-human clinical trial of iPSC-derived platelets as a phase 1 autologous transfusion study.

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Long-term follow-up of VIALE-C in patients with untreated AML ineligible for intensive chemotherapy.

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Morphologic findings often provide guidance when immunophenotypic data overlap: a case of AML with cup-shaped nuclei.

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Sadler B, Christopherson PA, Haller G, Montgomery RR, Di Paola J; Zimmerman Program Investigators. von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. Blood. 2021;137(23):3277-3283.

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Single Cell Genomics - a new chapter in how technological advances propel Hemato-Oncology.

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Timing of allo-HCT in CMML.

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Tumburu L, Ghosh-Choudhary S, Seifuddin FT, et al. Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease. Blood. 2021;137(22):3116-3126.

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Blood Adv

Do sophisticated models give the full picture of allogeneic hematopoietic stem cell transplantation effect?

Pubmed   Journal   ReadQx 

Leukemia

A Phase II prospective trial of azacitidine in steroid-dependent or refractory systemic autoimmune/inflammatory disorders and VEXAS syndrome associated with MDS and CMML.

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IgM-secreting diffuse large B-cell lymphoma: results of a multicentre clinicopathological and molecular study.

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Ixazomib, lenalidomide and dexamethasone consolidation with randomized ixazomib or lenalidomide maintenance after autologous transplant in newly diagnosed multiple myeloma.

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Thromb Haemost

A Trp11Arg Substitution in the ß3 Signal Peptide Prevents Expression of aIIbß3 in Patients with Glanzmann Thrombasthenia.

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Letters&Replies

Letters to the editors and authors’ replies

Am J Hematol

A reply to Moris et al.

Pubmed   Journal   ReadQx 

Determinants of early triage for hospitalization in MPN patients with COVID-19.

Pubmed   Journal   ReadQx 

Increased CD8 T-cell immunity after COVID-19 vaccination in lymphoid malignancy patients lacking adequate humoral response: An immune compensation mechanism?

Pubmed   Journal   ReadQx 

Secondary-type mutations do not impact prognosis in AML with mutated NPM1.

Pubmed   Journal   ReadQx 

Ann Oncol

Liquid versus tissue biopsy for detecting actionable alterations according to ESCAT in patients with advanced cancer: A study from the French National Center for Precision Medicine (PRISM).

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Reply to the Letter to the Editor "Risk-adapted modulation through de-intensification of cancer treatments: an ESMO classification" by Hannoun-Levi et al.

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T Cell Receptor Sequencing Reveals Reduced Clonal Breadth of T Cell Responses against SARS-CoV-2 after Natural Infection and Vaccination in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

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Blood Cancer J

The prognostic value of the MASS in a multi-center cohort of patients with newly diagnosed multiple myeloma.

Pubmed   Journal   ReadQx   PMC